A clinical study of a new FMT method using hydrogen nanobubble water (NanoGAS® water) without antimicrobial agents has been initiated.

April 20, 2023

Clinical Study on the Efficacy and Safety of a Novel Fecal Microbiota Transplantation Method for
Clinical Study on the Efficacy and Safety of a Novel Fecal Microbiota Transplantation Method for Autism Spectrum Disorders

 

Clinical research has been initiated by physicians and others affiliated with our research group.

The information is available on jRCT (Japanese Research Reporting and Release System for Clinical Research).
https://jrct.niph.go.jp/latest-detail/jRCTs031230041

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Summary ( based on jRCT public information)

1. Purpose and content of clinical research

Purpose of the study

The purpose of this clinical study is to clarify the efficacy and safety of “a novel fecal microbiota transplantation (FMT) method using a fecal microbiota solution (SHIN-1) prepared with hydrogen nanobubble water” for autism spectrum disorder (ASD).
This FMT method is being developed as a new method that does not require administration of antimicrobial agents or intestinal cleansing prior to FMT, which has been done in previous studies, and that can be performed with a small dose (about 1/1000 of the dose (number of bacteria) used in those studies).

DIFFERENCE BETWEEN THE NEW FMT METHOD AND THE CONVENTIONAL FMT METHOD (CONCEPTUAL DIAGRAM)

 

Phase of study
1. Clinical research in the early stages of research and development

Planned research period
April 18, 2023 – March 31, 2025

Number of planned research subjects
30

Study design
Multicenter, non-randomized, open-label, single-arm, before/after study

Target disease name
Autism Spectrum Disorders

Selection criteria
1. children between the ages of 5 and 12 with a diagnosis of ASD made by a pediatric neurologist, a board-certified specialist in neuropsychiatry, a board-certified child and adolescent psychiatrist, or a board-certified pediatric psychiatrist (certificate of diagnosis required; gender is not specified) ^{(Note 1)}.
　A list of pediatric neurologists certified by the Japanese Society of Pediatric Neurology:
https://www.childneuro.jp/modules/senmoni/
2. In generally good physical health except for gastrointestinal symptoms (as determined by the principal investigator ^{(Note 2)} ).
3. A written statement of participation in the study, 3. who can give consent to participate in this study in writing, or by illustration or verbal explanation if necessary.
4. who can obtain written consent from a surrogate to participate in this study. 

Exclusion Criteria
1. patients undergoing medical treatment 2. patients who have received antibiotics (excluding topical antibiotics) within the past 3 months
2. has received antibiotics (except topical antibiotics) within the past 3 months 3. has received a fecal microbiota transplant within the past 12 months
Patients who have received a fecal microbiota transplant within the past 12 months. 4.
4. has a single-gene disorder with ASD-like symptoms (Fragile X syndrome, Rett syndrome, Joubert syndrome, or other conditions that may affect efficacy determination).
5. has neurosurgical or neurological disease.
6. is on tube feeding.
7. is underweight/undernourished by less than 65% of standard weight. Underweight/undernourished.
8. who have had surgery within the past year or are scheduled to have surgery within the next six months.
9. who are currently participating in another clinical trial.
10. who are otherwise determined by the principal investigator to be unsuitable as research subjects. 11. who are currently participating in a clinical trial. 

Protocol Treatment
1. Schedule for administration of SHIN-1-containing intravenous solution
SHIN-1-containing intravenous solution will be administered intravenously once per week for a total of 6 consecutive weeks. The final evaluation of efficacy will be made with the results of Week 30 after the start of administration.
2. Contents of SHIN-1-containing intravenous solution to be administered each week
The contents of the intravenous solution to be administered in each week from Week 1 to Week 6 are as follows. The amount of undiluted SHIN-1 solution to be administered in each week from Week 1 to Week 6 will be set at 3 g, 5 g, 7 g, 9 g, 11 g, and 13 g, respectively, in that order, and six types of intravenous solutions adjusted by adding 100 g of saline solution to each. 

Select and use a thin rubberized intravenous tube (6.5 mm diameter) for intravenous administration, taking into account that the patient is an infant.

Discontinuation Criteria

＜Discontinuation of research on research subjects＞
The principal investigator will discontinue research on research subjects if, after enrollment, it is found that the research subject
　1. an adverse event occurs and the principal investigator determines that continuation of the research poses an unacceptable risk to the health of the research subject; or 2. the research subject requests that the research be discontinued.
　(2) If the research subject requests discontinuation of the research. 3.
　3. when concomitant medications or therapies are used, but not discontinued if the Efficacy and Safety Evaluation Committee determines that the concomitant medications or therapies will not affect the results of this study.
　4. if the subject is found to be inappropriate as a research subject　
　5. when it is found impossible to conduct necessary observations or examinations for the convenience of the research subject; or
　6. other cases in which the principal investigator determines that the intervention should be discontinued.

＜Discontinuation of the entire clinical study＞
The principal investigator will discontinue or suspend the research as necessary if any of the following occurs: 1.
　(1) When new serious information is obtained that may adversely affect the safety of the research subjects or the conduct of the study, such as when anticipated adverse events (diseases, etc.) or failures significantly exceed those anticipated at the time of planning. (2) When extremely difficult to achieve the targeted number of research subjects, such as when enrollment of research subjects is significantly slower than planned.
　(2) When it is judged to be extremely difficult to achieve the target number of research subjects, such as when the enrollment of research subjects is significantly slower than planned.
　(3) If an opinion is received from an accredited clinical research review committee that this research should be terminated.
　4. other circumstances necessitating discontinuation or suspension of this study.

Primary Endpoints
1. SRS-2
1) The amount of change in ASD severity and the amount of change in severity of core symptoms will be analyzed.

THE “NOVEL FMT METHOD USING SHIN-1” SHOWED SIGNIFICANT REDUCTION OF ASD SYMPTOMS IN 10 OF 14 PATIENTS (71%), INCLUDING 6 SEVERE CASES, AT 8 WEEKS AFTER TRANSPLANTATION.

Secondary Endpoints
1 . Gazefinder ^{(Note 3} )
1) Analyzes the amount of change in ASD severity before and after FMT by the rate of gazing into specific areas.
2. PHQ-4
1) Consists of a “4-item scale of depression and anxiety.
3. GSRS (Gastrointestinal Symptom Rating Scale)
1) A questionnaire consisting of 15 items assessing digestive tract symptoms.
4. BS Score (Bristol Stool Form Scale, a record of changes in stool condition)
1) It is an index that classifies stool into 7 levels according to shape, color, and firmness.
5. Number and Frequency of Adverse Events Adverse events are evaluated when they are observed. 

 

(Note 1) Reason for setting the age of the study subjects (ASD children) between 5 and 2 years old
There is a consensus among pediatricians and psychiatrists worldwide that the starting point for support for people with ASD should be as early as possible (Zwaigenbaum L et al Pediatrics 136, 2015, Suppl 1, S10-40. etc.). On the other hand, when using children as research subjects, sufficient ethical considerations, respecting children’s human rights, are necessary to select subjects for whom informed consent can be obtained: a research study on the communication functions (comprehension and expression) of 4- and 5-year-old children with ASD (Bal et al . Autism. Res, 2018. etc.) have shown that communicative function improves significantly by age 5, such as “being able to select objects to which to direct attention in a purposeful and voluntary manner” once the child is 5 years old. Based on these findings, it is believed that 5-year-olds are capable of communicating assent, and 5 years of age was set as the lower age limit. As the age of the child increases, the characteristics of ASD cause conflicts with society, which trigger excessive stress and trauma suffered by the individual, resulting in various secondary disorders such as anxiety and depression, which become more difficult to treat. In elementary schools, there are also special support schools, which create an environment where secondary disorders are less likely to occur. For these reasons, the upper age limit was set at 12 years. This selection criterion was set in consideration of ethical considerations and as an age at which further secondary disorders are less likely to occur.

IN THE PREVIOUS STUDIES CONDUCTED IN THE U.S. AND CHINA ON “FMT FOR THE TREATMENT OF CHILDREN WITH ASD,” AS WELL AS IN THE ONGOING (OR REGISTERED) “CLINICAL STUDIES AND ADVANCED CLINICAL TRIALS” IN THE U.S. AND CHINA, THE AGE OF STUDY SUBJECTS HAS BEEN REDUCED TO 2 AND 3 YEARS, RESPECTIVELY, AS SHOWN IN THE TABLE BELOW.

Table Age Range of Study Subjects in Prior Studies and Ongoing (or Enrolled) Clinical Trials

Implementing agency	stage	Age Range of Study Subjects
University of Arizona	Prior Clinical Studies	7-17 years old
Third Military Medical University	Prior Clinical Studies	3-17 years old
ProgenaBiome	clinical trial	2 years old or up
Ventura C.Trials	clinical trial	2 years old or up
LA Children’s Hospital	clinical trial	5-17 years old
University of Arizona	clinical trial	5-17 years old
wuhan university	clinical trial	3-18 years old

(Note 2) Selection of Principal Investigators (6 sites )
Physicians with experience (at least 3 cases) in performing “novel fecal microbiota transplantation (FMT) using fecal microbiota solution (SHIN-1)” for children with ASD under free medical care were selected.

Medical Corporation Nizenkai Tanaka Clinic	1F Denki Kan Building, 2-3-8 Ikunonishi, Ikuno-ku, Osaka, Japan 06-6711-3770	Yoshinori Tanaka	board Chairman	https://www.tanaka-cl.com/fmt.html
Luke’s Ashiya Clinic	8-2 Oharacho, Ashiya-shi, Hyogo, Japan 0797-23-6033	Masahiko Shirotani	director	https://www.lukesashiya.com/feature/flora.html
Medical Corporation Kiwakai Kitamura Clinic	4-3-8 Nishiki-cho, Onojo-shi, Fukuoka, Japan 092-581-6640	Kunihiro Kitamura	director	http://www.kitamura.or.jp/contents_fmt.html
Medical Corporation Yuakai Cute Internal Medicine Clinic	3-7-14 Higashinakahama, Joto-ku, Osaka City, Osaka, Japan 06-6962-3133	Yuichi Kawai	board Chairman	https://www.kawai-medical.com/diagnosis02/
Futamatakai Medical Corporation Natural Art Clinic	Android Building 2F, 6-5 Rokubancho, Chiyoda-ku, Tokyo 03-6256-8448	Yasuhito Mikawa	director	https://naturalartclinic.com/alternative-therapy/1549
Medical Corporation Haruna Clinic	1-3-13-202 Nishimikuni, Yodogawa-ku, Osaka-shi, Osaka 06-4807-5130	Reiko Haruna	vice president (of a hospital, clinic, etc.)	https://www.haruna-clinic.com/541-2

(Note 3) Gazefinder
This device is one tool to objectively evaluate ASD characteristics based on the way a person looks at things, such as where he/she was looking at a 2-minute video. The test can be performed by simply looking at the screen, making the test less burdensome for the child. This device is attracting attention as the world’s first autism spectrum disorder diagnostic aid that combines objectivity and quantitativeness. This technology was developed by Professor Kenji Tsuchiya of Hamamatsu University School of Medicine and Professor Taiichi Katayama of Osaka University School of Medicine, who are participating in this clinical study. JVC KENWOOD Corporation is currently applying for approval in Australia and Japan.

(IMAGE COURTESY OF JVC KENWOOD CORPORATION)

2. Schematic diagram of the study (Schema)

Open-label, before-after comparative study

<前後比較試験を選択した理由＞

1) This clinical study is an exploratory clinical study in the early stages of development, and since the study subjects are infants, it was decided to conduct a single-arm, pre/post comparison study without a control group, taking ethical considerations into account.

2) THE REASON FOR STATING THAT “A PRE- AND POST-COMPARATIVE STUDY CAN DEMONSTRATE EFFICACY IN THIS CLINICAL STUDY” IS THAT EVEN IF THE ASD CHILD CONTINUES TO RECEIVE MEDICAL CARE DURING THE STUDY PERIOD, IT “WILL NOT AFFECT THE RESULTS OF THIS STUDY.” THE REASONS FOR THIS ARE AS FOLLOWS.　　　

TACHIBANA ET AL. OF THE NATIONAL CENTER FOR CHILD HEALTH AND DEVELOPMENT AND TACHIBANA ET AL. REPORTED THAT A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS ON THE EFFECTS OF ASD REHABILITATION PROGRAMS IN JAPAN AND OVERSEAS SHOWED NO DIFFERENCES IN OUTCOMES SUCH AS ASD SEVERITY, DEVELOPMENTAL INDEX, RECEPTIVE LANGUAGE, AND EXPRESSIVE LANGUAGE DEPENDING ON THE REHABILITATION PROGRAM.

3) PREVIOUS STUDIES ON THE EFFICACY OF FMT FOR ASD AT THE UNIVERSITY OF ARIZONA IN THE U.S. AND AT THE THIRD MILITARY MEDICAL UNIVERSITY IN CHINA HAVE ALSO BEEN CONDUCTED IN PRE- AND POST-COMPARATIVE STUDIES.

3. Exploratory endpoint: 16S rRNA gene analysis of ASD children and intestinal microbiota composition

16S rRNA gene analysis of the intestinal microbiota composition of children with ASD shall be performed at the following time points.

＜Analysis Period＞

 BEFORE FMT ・8 WEEKS AFTER FMT ・30 WEEKS AFTER FMT　

BASED ON PREVIOUS STUDIES, WE HAVE FOUND THAT THE COMPOSITION OF THE INTESTINAL MICROBIOTA OF CHILDREN WITH ASD HAS FIVE CHARACTERISTICS THAT DIFFER FROM THOSE OF CHILDREN WITH TYPICAL DEVELOPMENT.

IN THIS CLINICAL STUDY, WE WILL EXAMINE THE DIAGNOSTIC POTENTIAL OF FIVE FEATURES FOR ASD.

4 . Use of “SHIN-1 prepared from the same accumulated stool” and lot control

IN THE PAST, SYMBIOSIS, IN COLLABORATION WITH OUR MEDICAL INSTITUTION, HAS ALREADY MANAGED LOTS OF RAW MATERIALS AND INTERMEDIATES IN THE TREATMENT OF ASD BY FMT. HOWEVER, IN ALL OF THESE CASES, DIFFERENT DONOR STOOLS WERE USED FOR EACH STUDY SUBJECT (ASD CHILD).

In this clinical study, SHIN-1 prepared from accumulated and stored stool from one donor in perfect health will be administered to 30 ASD children. In other words, all children with ASD will be administered SHIN-1 with the same fecal microbiota in this clinical study.
Lot management will be the same as before.
Lot numbers will be assigned to the accumulated stools and SHIN-1 from one healthy donor, and the results of various examinations and medical examinations of the healthy donor, stool examination and 16S rRNA gene analysis including infections in donor stools, as well as (anonymized) pre- and post-transplant examination results (primary endpoint, secondary endpoints, and 16S rRNA gene analysis) of the study subjects will be analyzed. The results of various tests before and after transplantation (primary endpoints, secondary endpoints, and results of 16S rRNA gene analysis of fecal samples) of research subjects (anonymized) shall be linked and stored for 20 years.

In addition to a portion of the fecal material used in the testing, serum, plasma, whole blood, and urine used in donor testing shall be stored at -80°C for at least 20 years.

5. Schedule for observation, examination, and evaluation

The principal investigator will collect data according to the “Observation and Testing Schedule. In principle, the same principal investigator will conduct the examination, observation, and evaluation of the research subjects.

Study Calendar

 

Contact: Secretariat of Clinical Research
E-mail: rinshokenkyu.jimukyoku@gmail.com
TEL: 06-6356-2220 FAX: 06-6777-2204 (weekdays 10:00 – 18:00)

Click here for inquiry form for recruitment of research collaborators
https:// fmt.sym-biosis.co.jp/news/notice/9282/